BACKGROUND: Endometrial cancer is one of the major gynecological cancers, with increasing incidence and mortality in the past decades. Emerging preclinical and clinical data have indicated its close association with obesity and dyslipidemia. Metabolism reprogramming has been considered as the hallmark of cancer, to satisfy the extensive need of nutrients and energy for survival and growth. Particularly, lipid metabolism reprogramming has aroused the researchers\' interest in the field of cancer, including tumorigenesis, invasiveness, metastasis, therapeutic resistance and immunity modulation, etc. But the roles of lipid metabolism reprogramming in endometrial cancer have not been fully understood. This review has summarized how lipid metabolism reprogramming induces oncogenesis and progression of endometrial cancer, including the biological functions of aberrant lipid metabolism pathway and altered transcription regulation of lipid metabolism pathway. Besides, we proposed novel therapeutic strategies of targeting lipid metabolism pathway and concentrated on its potential of sensitizing immunotherapy and hormonal therapy, to further optimize the existing treatment modalities of patients with advanced/metastatic endometrial cancer. Moreover, we expect that targeting lipid metabolism plus hormone therapy may block the endometrial malignant transformation and enrich the preventative approaches of endometrial cancer.
CONCLUSIONS: Lipid metabolism reprogramming plays an important role in tumor initiation and cancer progression of endometrial cancer. Targeting the core enzymes and transcriptional factors of lipid metabolism pathway alone or in combination with immunotherapy/hormone treatment is expected to decrease the tumor burden and provide promising treatment opportunity for patients with advanced/metastatic endometrial cancer.

BACKGROUND: iPSC reprogramming technology exhibits significant promise in the realms of clinical therapeutics, disease modeling, pharmaceutical drug discovery, and various other applications. However, the extensive utilization of this technology has encountered impediments in the form of inefficiency, prolonged procedures, and ambiguous biological processes. Consequently, in order to improve this technology, it is of great significance to delve into the underlying mechanisms involved in iPSC reprogramming. The BET protein BRD4 plays a crucial role in the late stage of reprogramming; however, its precise function in the early stage remains unclear.
RESULTS: Our study aims to investigate BRD4\'s role in the early stages of iPSC reprogramming. Our investigation reveals that early inhibition of BRD4 substantially enhances iPSC reprogramming, whereas its implementation during the middle-late stage impedes the process. During the reprogramming, ribosome DNA expression initially increases before decreasing and then gradually recovers. Early inhibition of BRD4 improved the decline and restoration of rDNA expression in the early and middle-late stages, respectively. Additionally, we uncovered the mechanism of BRD4\'s regulation of rDNA transcription throughout reprogramming. Specifically, BRD4 interacts with UBF and co-localizes to both the rDNA promoter and enhancer regions. Ultimately, BRD4 facilitates rDNA transcription by promoting the enrichment of histone H3 lysine 27 acetylation in the surrounding chromatin. Moreover, we also discovered that early inhibition of BRD4 facilitates cells\' transition out of the somatic cell state and activate pluripotent genes.
CONCLUSIONS: In conclusion, our results demonstrate that early inhibition of BRD4 promotes sequential dynamic expression of rDNA, which improves iPSC reprogramming efficiency.

Metabolic reprogramming provides tumors with an energy source and biofuel to support their survival in the malignant microenvironment. Extensive research into the intrinsic oncogenic mechanisms of the tumor microenvironment (TME) has established that cancer-associated fibroblast (CAFs) and metabolic reprogramming regulates tumor progression through numerous biological activities, including tumor immunosuppression, chronic inflammation, and ecological niche remodeling. Specifically, immunosuppressive TME formation is promoted and mediators released via CAFs and multiple immune cells that collectively support chronic inflammation, thereby inducing pre-metastatic ecological niche formation, and ultimately driving a vicious cycle of tumor proliferation and metastasis. This review comprehensively explores the process of CAFs and metabolic regulation of the dynamic evolution of tumor-adapted TME, with particular focus on the mechanisms by which CAFs promote the formation of an immunosuppressive microenvironment and support metastasis. Existing findings confirm that multiple components of the TME act cooperatively to accelerate the progression of tumor events. The potential applications and challenges of targeted therapies based on CAFs in the clinical setting are further discussed in the context of advancing research related to CAFs.

Triple-negative breast cancer (TNBC) has become a thorny problem in the treatment of breast cancer because of its high invasiveness, metastasis and recurrence. Although immunotherapy has made important progress in TNBC, immune escape caused by many factors, especially metabolic reprogramming, is still the bottleneck of TNBC immunotherapy. Regrettably, the mechanisms responsible for immune escape remain poorly understood. Exploring the mechanism of TNBC immune escape at the metabolic level provides a target and direction for follow-up targeting or immunotherapy. In this review, we focus on the mechanism that TNBC affects immune cells and interstitial cells through hypoxia, glucose metabolism, lipid metabolism and amino acid metabolism, and changes tumor metabolism and tumor microenvironment. This will help to find new targets and strategies for TNBC immunotherapy.

Induced pluripotent stem cells (iPSCs) that are generated from adult somatic cells are induced to express genes that make them pluripotent through reprogramming techniques. With their unlimited proliferative capacity and multifaceted differentiation potential and circumventing the ethical problems encountered in the application of embryonic stem cells (ESC), iPSCs have a broad application in the fields of cell therapy, drug screening, and disease models and may open up new possibilities for regenerative medicine to treat diseases in the future. In this review, we begin with different reprogramming cell technologies to obtain iPSCs, including biotechnological, chemical, and physical modulation techniques, and present their respective strengths, and limitations, as well as the recent progress of research. Secondly, we review recent research advances in iPSC reprogramming-based regenerative therapies. iPSCs are now widely used to study various clinical diseases of hair follicle defects, myocardial infarction, neurological disorders, liver diseases, and spinal cord injuries. This review focuses on the translational clinical research around iPSCs as well as their potential for growth in the medical field. Finally, we summarize the overall review and look at the potential future of iPSCs in the field of cell therapy as well as tissue regeneration engineering and possible problems. We believe that the advancing iPSC research will help drive long-awaited breakthroughs in cellular therapy.

OBJECTIVE: To establish a methodological system for reprogramming rat embryonic fibroblasts (REF) into chemically induced neurons (ciNCs) via small molecule compounds to provide safe and effective donor cells for treatment of neurodegenerative diseases.
METHODS: Based on the method established by PEI Gang\'s research group to directly reprogram human fibroblasts into neurons, the induction medium and maturation medium was optimized by replacing the coating solution, mitigating oxidative stress injury, adding neurogenic protective factors, adjusting the concentration of trichothecenes, performing small-molecule removal experiments, and carrying out immunofluorescence and Western blotting on cells at different stages of induction to validate the effect of induction.
RESULTS: When the original protocol was used for induction, the cell survival rate was (34.24±2.77)%. After replacing the coating solution gelatin with matrigel, the cell survival rate increased to (45.41±4.27)%; after adding melatonin, the cell survival rate increased to (67.95±5.61)% and (23.43±1.42)% were transformed into neural-like cells; after adding the small molecule P7C3-A20, the cell survival rate was further increased to (76.27±1.41)%, and (39.72±4.75)% of the cells were transformed into neural-like cells. When the concentration of trichothecene was increased to 30 μmol/L, the proportion of neural-like cells reached (55.79±1.90)%; after the removal of SP600125, (86.96±2.15)% of the cells survived, and the rate of neural-like cell production increased to (63.43±1.60)%. With the optimized protocol, REF could be successfully induced into ciNC through the neural precursor cell stage, in which the neural precursor cells were able to highly express the neural precursor cell markers SRY-related HMG-box gene 2 (Sox2) and paired box 6 (Pax6) as well as neuron-specific marker tubulin 1 (Tuj1), while the expression of fiber-associated protein vimentin was reduced. After two weeks of induction of neural precursor cells in a maturation medium, most cells displayed neuronal-like cell morphology. The induced ciNCs were able to highly express the mature neuronal surface markers Tuj1 and microtubule-associated protein 2 (MAP2), while the expression of vimentin was reduced.
CONCLUSIONS: The small molecule combinations optimized in this study can reprogram REF to ciNCs under normoxic conditions.
目的: 建立通过小分子化合物将大鼠胚胎成纤维细胞（REF）重编程为化学诱导神经元（ciNC）的方法体系，为细胞移植治疗神经退行性疾病提供安全有效的供体细胞。方法: 以裴钢研究团队建立的人成纤维细胞直接重编程为神经元的方法为基础，通过更换包被液、缓解氧化应激损伤、添加神经源性保护因子、调整毛喉素浓度和小分子去除实验对诱导培养基和成熟培养基进行优化，并通过免疫荧光法和蛋白质印迹法验证不同诱导阶段细胞的相关蛋白质。结果: 以原方案进行诱导时，细胞存活率仅（34.24±2.77）%。包被液更换为基质胶后，细胞存活率上升到（45.41±4.27）%；添加褪黑素后细胞存活率提高至（67.95±5.61）%，（23.43±1.42）%的细胞转变为神经样细胞；添加小分子P7C3-A20后细胞存活率进一步提升至（76.27±1.41）%，（39.72±4.75）%的细胞转变为神经样细胞；毛喉素浓度提升至30 μmol/L时，神经样细胞比例达到（55.79±1.90）%；去除SP600125后，（86.96±2.15）%细胞存活，神经样细胞生成率提高至（63.43±1.60）%。以优化后的方案诱导，可经过神经前体细胞将REF诱导为ciNC。其中，神经前体细胞能够高表达神经前体细胞标志物SRY-box转录因子2、配对盒6以及神经元特异性标志物Ⅲ类β-微管蛋白，而成纤维相关蛋白波形蛋白表达量减少。神经前体细胞在成熟培养基中诱导两周后，可见大部分细胞呈神经样细胞形态，诱导后的ciNC高表达Ⅲ类β-微管蛋白和微管相关蛋白2，而成纤维相关蛋白波形蛋白表达减少。结论: 优化后的小分子组合在常氧条件下能将REF重编程为ciNC。.

Hematopoietic stem cells (HSCs) exhibit significant functional and metabolic alterations within the lung cancer microenvironment, contributing to tumor progression and immune evasion by increasing differentiation into myeloid-derived suppressor cells (MDSCs). Our aim is to analyze the metabolic transition of HSCs from glycolysis to oxidative phosphorylation (OXPHOS) in lung cancer and determine its effects on HSC functionality. Using a murine Lewis Lung Carcinoma lung cancer model, we conducted metabolic profiling of long-term and short-term HSCs, as well as multipotent progenitors, comparing their metabolic states in normal and cancer conditions. We measured glucose uptake using 2-[N-(7-Nitrobenz-2-oxa-1,3-diazol-4-yl)Amino]-2-Deoxyglucose (2-NBDG) and assessed levels of lactate, acetyl-coenzyme A, and ATP. Mitochondrial functionality was evaluated through flow cytometry, alongside the impact of the glucose metabolism inhibitor 2-DG on HSC differentiation and mitochondrial activity. HSCs under lung cancer conditions showed increased glucose uptake and lactate production, with an associated rise in OXPHOS activity, marking a metabolic shift. Treatment with 2-DG led to decreased T-HSCs and MDSCs and an increased red blood cell count, highlighting its potential to influence metabolic and differentiation pathways in HSCs. This study provides novel insights into the metabolic reprogramming of HSCs in lung cancer, emphasizing the critical shift from glycolysis to OXPHOS and its implications for the therapeutic targeting of cancer-related metabolic pathways.

Macrophages play crucial roles in the innate immune response, exhibiting context-dependent behaviors. Within the tumor microenvironment, macrophages exist as tumor-associated or M2-like macrophages, presenting reprogramming challenges. In this study, we develop a peptide hydrogel that is able to polarize M0 macrophages into pro-inflammatory M1 macrophages through the activation of NF-κB signaling pathways. Importantly, this system is also found to be capable of reprogramming M2 macrophages into pro-inflammatory M1-like macrophages by activating CD206 receptors. The nanofibrous hydrogel self-assembles from a short peptide that contains an innate defense regulator peptide and a self-assembly promoting motif, presenting densely arrayed regulators that multivalently engage with macrophage membrane receptors to not only polarize M0 macrophages but also repolarize M2 macrophages into M1-like macrophages. Overall, this work offers a promising strategy for reprogramming macrophages, holding the potential to enhance immunotherapy by remodeling immune-resistant microenvironments.

BACKGROUND: Despite considerable progress in cancer immunotherapy, it is not available for many patients. Resistance to immune checkpoint blockers arises from the intricate interactions between cancer and its microenvironment. Metabolic reprogramming in tumor and immune cells in the tumor microenvironment (TME) influences anti-tumor immune responses by remodeling the immune microenvironment. Metabolic reprogramming has emerged as an important hallmark of tumorigenesis. However, few studies have focused on the TME and metabolic reprogramming. Therefore, we aimed to explore the current research status and popular topics in TME-related metabolic reprogramming over a 20 years using a bibliometric approach.
METHODS: Studies focusing on metabolic reprogramming and TME were searched using the Web of Science Core Collection database. Bibliometric and visual analyses of the articles and reviews were performed using Bibliometrix, VOSviewer, and CiteSpace.
RESULTS: In total, 4726 articles published between 2003 and 2022 were selected. The number of publications and citations has increased annually. Cooperation network analysis indicated that the United States holds the foremost position in metabolic reprogramming and TME research with the highest volume of publications and citations, thus exerting the greatest influence. Among these institutions, Fudan University displayed the highest level of productivity. Frontiers in Immunology showed the highest degree of productivity in this field. Ho Ping-Chih made the most article contributions, and Pearce Edward J. was the most co-cited author. Four clusters were obtained after a cluster analysis of the authors\' keywords: TME, metabolic reprogramming, immunometabolism, and immunity. Immunometabolism, glycolysis, immune cells, and tumor-associated macrophages are relatively recent keywords that have attracted increasing attention.
CONCLUSIONS: A comprehensive landscape of advancements in metabolic reprogramming and the TME was evaluated, which provided crucial information for scholars to further advance this promising field. Further research should explore new topics related to immunometabolism in the TME using a transdisciplinary approach.

Recent advances in single-cell sequencing technology have revolutionized our ability to acquire whole transcriptome data. However, uncovering the underlying transcriptional drivers and nonequilibrium driving forces of cell function directly from these data remains challenging. We address this by learning cell state vector fields from discrete single-cell RNA velocity to quantify the single-cell global nonequilibrium driving forces as landscape and flux. From single-cell data, we quantified the Waddington landscape, showing that optimal paths for differentiation and reprogramming deviate from the naively expected landscape gradient paths and may not pass through landscape saddles at finite fluctuations, challenging conventional transition state estimation of kinetic rate for cell fate decisions due to the presence of the flux. A key insight from our study is that stem/progenitor cells necessitate greater energy dissipation for rapid cell cycles and self-renewal, maintaining pluripotency. We predict optimal developmental pathways and elucidate the nucleation mechanism of cell fate decisions, with transition states as nucleation sites and pioneer genes as nucleation seeds. The concept of loop flux quantifies the contributions of each cycle flux to cell state transitions, facilitating the understanding of cell dynamics and thermodynamic cost, and providing insights into optimizing biological functions. We also infer cell-cell interactions and cell-type-specific gene regulatory networks, encompassing feedback mechanisms and interaction intensities, predicting genetic perturbation effects on cell fate decisions from single-cell omics data. Essentially, our methodology validates the landscape and flux theory, along with its associated quantifications, offering a framework for exploring the physical principles underlying cellular differentiation and reprogramming and broader biological processes through high-throughput single-cell sequencing experiments.